1. Field of the Invention
This invention relates to a pharmaceutical composition of extended release formulation comprising hard gelatin capsule containing therapeutically effective amount of mini-tablets wherein each mini-tablet comprises venlafaxine hydrochloride, microcrystalline cellulose, binder and optionally conventional excipients.
2. Related Art of the Invention
The use of hydrophobic polymers to produce extended or controlled release pharmaceutical composition is known in the art. For extending the release, the solid dosage form of mini-tablets comprising a drug is coated with hydrophobic polymer and pore forming agent. As soon as solid dosage form comes in contact with surrounding media, the pores are formed and the drug is diffused through these pores. Control of the rate of release benefits therapy by producing constant blood plasma levels of the active ingredient and by decreasing the frequency of administration, thereby improving patient compliance to the dosage regimen. The present invention provides a pharmaceutical composition of extended release capsule containing mini-tablets of venlafaxine hydrochloride suitable for once daily administration to human subjects.
The invention relates to an extended release pharmaceutical formulation for once daily administration, in particular to a controlled release pharmaceutical formulation of venlafaxine hydrochloride.
Several extended release drug delivery system adapted for the delivery of venlafaxine hydrochloride are known in the prior art.
U.S. Pat. No. 4,535,186 describes a class of hydroxycycloalkanephenethyl amines as being useful antidepressants and exemplifies the compound now known as venlafaxine hydrochloride as one of the suitable species.
Venlafaxine, is chemically named as (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol. Presently venlafaxine hydrochloride is administered to adults as conventional immediate release tablets or as 24 hours extended-release multiparticulate capsules. Venlafaxine hydrochloride is approved for sale in various countries including the United States of America under the brand name EFFEXOR™ (Wyeth Ayerst). It is available as an immediate release tablet and as an extended release capsule under the brand name EFFEXOR™ (Wyeth Ayerst) and EFFEXOR XR™ (Wyeth Ayerst), respectively.
Venlafaxine hydrochloride is very soluble in water. It is known that it is very difficult to develop a pharmaceutical form with a very slow dissolution rate of freely soluble drug.
U.S. Pat. No. 6,274,171 and related EP 0797991 disclose encapsulated extended release formulations form venlafaxine hydrochloride. A once daily, encapsulated extended release dosage form is disclosed that provides a flattened drug plasma profile and reduces the adverse side effects. The encapsulated dosage form is taught to comprise spheroids of venlafaxine hydrochloride, microcrystalline cellulose, and hydroxypropylmethylcellulose (HPMC). These spheroids are coated with a mixture of ethyl cellulose and HPMC. By providing an appropriate amount of the coating, the desired blood plasma profile can be obtained.
U.S. Pat. No. 6,274,171 and EP 0797991 also state that forming an extended release dosage from of venlafaxine hydrochloride was difficult in part due to the high water solubility of the hydrochloride salt. In fact, these patents disclose that “[n]umerous attempts to produce extended release tablets by hydrogel technology proved to be fruitless because the compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies.” Unlike the encapsulated extended release formulations described in these patents, a hydrogel extended release venlafaxine hydrochloride tablet is taught to typically exhibit a dissolution profile wherein 40%-50% is released within 2 hours, 60%-70% is released within 4 hours, and 85%-100% is released within 8 hours.
WO99/22724 also discloses encapsulated venlafaxine hydrochloride extended release dosage forms. These formulations differ from those in U.S. Pat. No. 6,274,171 and EP 0797991 in that the spheroid is substantially free of HPMC.
Although a venlafaxine extended release capsule has been produced, it would be advantageous to provide a less complicated dosage form that nonetheless provides extended release of venlafaxine.
WO94/27589 and WO01/37815 describe osmotic dosage forms containing venlafaxine hydrochloride.
US 20030190354 discloses an extended release composition comprising as active compound venlafaxine hydrochloride in a matrix tablet dosage form, in which venlafaxine hydrochloride is mixed with a combination of hydrophilic and hydrophobic matrix forming components. The matrix components are suitably combination of high and low viscosity grades hydroxyl propyl methyl cellulose, ethyl cellulose, glyceryl behenate and methyl cellulose. Two granulation methods were used for the production of the tablets: the first was a regular one step granulation process, in which all excipients were blended together with the active, then wet granulated with Kollidon SR, dried, milled and compressed into oval shape scored tablets. The second granulation process was a two step process, the first was wet granulation of the active material, which was blended with the hydrophobic components selected from Ethocel or Compritol. Later on, the milled granulate was mixed with the hydrophilic components, the methocels and the lubricating components, syloid 244 and Mg stearate.
WO03/55475 teaches the controlled release formulation of venlafaxine. The pharmaceutical formulation of the present invention comprises for example a core consisting of an active drug which may be advantageously in amorphous form, polyvinylpyrrolidone, a combination of two hydrophilic polymers having different viscosity and optionally other commonly used ingredients for solid dosage forms. The core is coated with a polymeric coating comprising a combination of two polymers having different water permeability. A plasticizer and other commonly used ingredients for film coating may be optionally added thereto. The combination of the carriers i.e. the water soluble polymer, polyvinylpyrrolidone and the low viscosity hydrophilic polymer has a double effect and the advantage that it stabilizes the amorphous form of the active ingredient and simultaneously modifies the release of the amorphous active ingredient in such a way that it is sustained, repeatable and independent of the amorphous or polymorphous form of the active ingredient, its particle size and specific surface area.
WO 03/53402 and related US 2004133982 discloses zero-order sustained release dosage forms. A solid dosage form comprising a matrix core comprising intragranular ethylcellulose and a water soluble active agent granulated and compressed together with extragranular ethyl cellulose and a film coating comprising a hydrophobic polymer wherein the film coating completely encases the matrix core. This invention also relates to a process for manufacturing a zero-order sustained release tablet containing a water-soluble active agent, comprising the steps of: (a) preparing a first admixture comprising the active agent and intragranular ethylcellulose; (b) granulating the first admixture in order to obtain a granular product; (c) preparing a second admixture comprising extragranular ethylcellulose; (d) preparing a third admixture comprising the granular product and the second admixture;
WO04/12699 and related US 20040096501 teach the use of dual retard technique to effectively control the release rate of modified release active ingredient by using small quantity of release controlling agents. This dual retard technique thus sufficiently reduces the size of the dosage form, which is convenient for swallowing. The dosage form comprises of a) Micro matrix particles containing high solubility active ingredient and one or more hydrophobic release controlling agent, b) Coating of Micro matrix particles with one or more hydrophobic release controlling agents.
Extended release preparation of drugs are advantageous in the administration because of their reduced dosage frequency. The frequency can be reduced by maintaining constant plasma concentration of drug over an extended period of time to ensure extended effect of active ingredient.